Ethanol (EtOH) has been well documented as an immunosuppressant and also a risk factor for various pulmonary infections. The first line of host defense in the alveolar space is the alveolar macrophage (AM). AM activation release tumor necrosis factor-alpha (TNF-alpha), which is critical for host immune defense. Our preliminary studies have shown that EtOH does not block TNF-alpha transcription in a human monocytic cell line. However, EtOH increases the expression of membrane-bound TNF-alpha precursor and decreases the secretion of mature TNF-alpha. Based on these findings, we propose to investigate whether EtOH targets post-translational processing (intracellular TNF-alpha transportation or TNF-alpha converting enzyme) in the process of TNF-alpha suppression. In addition, we propose to test whether introduction of TACE via adenoviral-mediated gene delivery can ameliorate EtOH-induced TNF-alpha suppression in human monocyte. The goal of this project is to develop a better understanding of the mechanisms of EtOH-induced immunosuppression, from which new therapeutic rationales can be developed in order to prevent such infections in high-risk individuals.